Method and apparatus for pain management using objective pain measure

ABSTRACT

An example of a system for managing pain may include a pain monitoring circuit, a pain relief device, and a control circuit. The pain monitoring circuit may include a parameter analyzer and a pain score generator. The parameter analyzer may be configured to receive and analyze at least two parameters selected from a physiological parameter indicative of a physiological function or state of a patient, a functional parameter indicative of a physical activity or state of the patient, or a patient parameter including subjective information provided by the patient. The pain score generator may be configured to compute a composite pain score using an outcome of the analysis. The composite pain score may indicate a degree of the pain. The pain relief device may be configured to deliver a pain-relief therapy. The control circuit may be configured to control the delivery of the pain-relief therapy using the composite pain score.

CLAIM OF PRIORITY

This application is a continuation of U.S. application Ser. No.15/688,676, filed Aug. 28, 2017, which claims the benefit of priorityunder 35 U.S.C. § 119(e) of U.S. Provisional Patent Application Ser. No.62/400,336, filed on Sep. 27, 2016, each of which is herein incorporatedby reference in their entirety.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is related to commonly assigned U.S. Provisional PatentApplication Ser. No. 62/400,313, entitled “SYSTEMS AND METHODS FORCLOSED-LOOP PAIN MANAGEMENT”, filed on Sep. 27, 2016 and U.S.Provisional Patent Application Ser. No. 62/395,641, entitled “METHOD ANDAPPARATUS FOR PAIN MANAGEMENT USING HEART SOUNDS”, filed on Sep. 16,2016, which are incorporated by reference in their entirety.

TECHNICAL FIELD

This document relates generally to medical devices and more particularlyto a pain management system that uses sensed physiological and/orfunctional parameters to produce an objective measure for pain.

BACKGROUND

Pain may result from an injury, a disease (e.g., arthritis,fibromyalgia), or even a medical treatment (e.g., certain cancertreatment). Various treatments are applied for pain management, such asmedication, psychotherapy, electrical stimulation, thermal therapy, andtheir various combinations. Examples of electrical stimulation for painmanagement include Transcutaneous Electrical Nerve Stimulation (TENS)delivered by a TENS unit and Spinal Cord Stimulation (SCS) that may bedelivered by an implantable neuromodulation systems. Pain treatment maybe prescribed based on an assessment of a patient's symptoms andunderlying conditioning and titrated based on the patient's response tothe treatment. As pain is not directly measurable by a machine, theassessment of the condition and the titration of the therapy may dependon questioning the patient.

SUMMARY

An example (e.g., “Example 1”) of a system for managing pain of apatient may include a pain monitoring circuit, a pain relief device, anda control circuit. The pain monitoring circuit may include a parameteranalyzer and a pain score generator. The parameter analyzer may beconfigured to receive and analyze at least two parameters selected froma physiological parameter indicative of a physiological function orstate of the patient, a functional parameter indicative of a physicalactivity or state of the patient, or a patient parameter includingsubjective information provided by the patient. The pain score generatormay be configured to compute a composite pain score using an outcome ofthe analysis. The composite pain score may indicate a degree of thepain. The pain relief device may be configured to deliver one or morepain-relief therapies. The control circuit may be configured to controlthe delivery of the one or more pain-relief therapies using thecomposite pain score and therapy parameters.

In Example 2, the subject matter of Example 1 may optionally beconfigured such that the parameter analyzer is configured to produce asignal metric using the at least two parameters, and the pain scoregenerator is configured to compute the composite pain score using thesignal metric.

In Example 3, the subject matter of Example 2 may optionally beconfigured such that the parameter analyzer is configured to generateone or more weighting factors and is configured to produce the signalmetric using the at least two parameters with the one or more weightingfactors each applied to a parameter of the at least two parameters.

In Example 4, the subject matter of Example 3 may optionally beconfigured such that the parameter analyzer is configured to adjust theone or more weighting factors by automatic adaptation to the patientover time.

In Example 5, the subject matter of any one or any combination ofExamples 1 to 4 may optionally be configured such that the painmonitoring circuit further include: one or more physiological signalsensors configured to sense one or more physiological signals from thepatient, a physiological signal sensing circuit configured to processthe one or more physiological signals, a physiological parametergenerator configured to generate the physiological parameter using theprocessed one or more physiological signals, one or more functionalsignal sensors to sense one or more functional signals from the patient,a functional signal sensing circuit configured to process the one ormore functional signals, and a functional parameter generator configuredto generate the functional parameter using the processed one or morefunctional signals.

In Example 6, the subject matter of Example 5 may optionally beconfigured such that the one or more physiological signal sensorsinclude a sensor configured to sense a physiological signal indicativeof change in sympathetic activity, and the physiological parametergenerator is configured to generate a physiological parameter being ameasure of the change in sympathetic activity.

In Example 7, the subject matter of Example 5 may optionally beconfigured such that the one or more physiological signal sensorsinclude a sensor configured to sense a physiological signal indicativeof a neural activity, and the physiological parameter generator isconfigured to generate a physiological parameter being a measure of theneural activity.

In Example 8, the subject matter of Example 5 may optionally beconfigured such that the one or more functional signal sensors include asensor configured to sense a function signal indicative of a measure ofmovement or posture, and the functional parameter generator isconfigured to generate a functional parameter quantitatively indicativethe measure of movement or posture.

In Example 9, the subject matter of any one or any combination ofExamples 1 to 8 may optionally be configured to include a patientinformation input device configured to receive patient informationrelated to pain, a patient information processing circuit configured toprocess the patient information, and a patient parameter generatorconfigured to generate the patient parameter using the processed patientinformation.

In Example 10, the subject matter of any one or any combination ofExamples 1 to 9 may optionally be configured such that the pain reliefdevice includes a neuromodulator to deliver a neuromodulation therapyincluding electrical stimulation.

In Example 11, the subject matter of any one or any combination ofExamples 1 to 10 may optionally be configured such that the pain reliefdevice includes a drug pump.

In Example 12, the subject matter of any one or any combination ofExamples 1 to 11 may optionally be configured to include an implantablemedical device including the pain monitoring circuit, the pain reliefdevice, and the control circuit, and the control circuit includes animplant control circuit.

In Example 13, the subject matter of Example 12 may optionally beconfigured to include an external device configured to becommunicatively coupled to the implantable medical device. The externaldevice includes the patient information input device including a patentinput device configured to receive a parameter representative ofintensity of the pain specified by the patient.

In Example 14, the subject matter of Example 13 may optionally beconfigured such that the external device is configured to receive thecomposite pain score, to produce a notification using the composite painscore, to determine one or more recipients of the notification using thecomposite pain score, and to control delivery of the notification toeach of the one or more recipients.

In Example 15, the subject matter of Example 14 may optionally beconfigured such that the external device is configured to produceexternal commands for adjusting the therapy parameters using thecomposite pain score and the patient information and transmit theexternal commands to the implantable medical device, and the implantcontrol circuit is configured to adjust the therapy parameters using theexternal commands.

An example (e.g., “Example 16”) of a method for managing pain of apatient is also provided. The method may include receiving and analyzingat least two parameter selected from a physiological parameterindicative of a physiological function or state of the patient, afunctional parameter indicative of a physical activity or state of thepatient, and a patient parameter related to the pain automatically usinga processor, the patient parameter including subjective informationprovided by the patient, computing a composite pain score using theprocessor based on an outcome of the analysis, the composite pain scoreindicating of a degree of the pain, delivering one or more pain-relieftherapies using a pain relief therapy device, and controlling thedelivery of the one or more pain-relief therapies from the pain relieftherapy device automatically using the processor based on the compositepain score and therapy parameters.

In Example 17, the subject matter of Example 16 may optionally furtherinclude generating one or more weighting factors, and the subject matterof analyzing the at least two parameters as found in Example 16 mayoptionally include generating a signal metric using the at least twoparameters with the one or more weighting factors each applied to aparameter of the at least two parameters, and the subject matter ofcomputing the composite pain score as found in Example 16 may optionallyinclude computing the composite pain score using the signal metric.

In Example 18, the subject matter of Example 17 may optionally furtherinclude adjusting the one or more weighting factors by automaticadaptation to the patient over time.

In Example 19, the subject matter of any one or any combination ofExample 16 may optionally further include sensing one or morephysiological signals from the patient using one or more physiologicalsignal sensors, generating the physiological parameter based the one ormore physiological signals using the processor, sensing one or morefunctional signals from the patient using one or more functional signalsensors, generating the functional parameter based the one or morefunctional signals using the processor, and receiving a parameterrepresentative of intensity of the pain from the patient.

In Example 20, the subject matter of generating the physiologicalparameter as found in Example 19 may optionally include generating ameasure of the change in sympathetic activity.

In Example 21, the subject matter of generating the physiologicalparameter as found in any one or any combination of Examples 19 and 20may optionally include generating a measure of the neural activity.

In Example 22, the subject matter of generating the functional parameteras found in any one or any combination of Examples 19 to 21 mayoptionally include generating a functional parameter quantitativelyindicative of a measure of movement or posture.

In Example 23, the subject matter of any one or any combination ofExamples 16 to 22 may optionally include producing a notification usingthe composite pain score, determining one or more recipients of thenotification using the composite pain score and one or more specifiedthresholds, and delivering the notification to each of the one or morerecipients.

In Example 24, the subject matter of delivering the one or morepain-relief therapies using the pain relief therapy device as found inany one or any combination of Examples 16 to 23 may optionally includedelivering one or more of a neuromodulation therapy including electricalstimulation or a drug therapy from an implantable medical device.

In Example 25, the subject matter of Example 24 may optionally furtherinclude adjusting the therapy parameters using the composite pain scoreand a patient command entered by the patient using an external devicecommunicatively coupled to the implantable medical device.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects of the disclosure will be apparent to persons skilled in the artupon reading and understanding the following detailed description andviewing the drawings that form a part thereof, each of which are not tobe taken in a limiting sense. The scope of the present disclosure isdefined by the appended claims and their legal equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings illustrate generally, by way of example, variousembodiments discussed in the present document. The drawings are forillustrative purposes only and may not be to scale.

FIG. 1 illustrates an embodiment of a pain analyzer.

FIG. 2 illustrates an embodiment of a pain monitoring circuit includinga pain analyzer such as the pain analyzer of FIG. 1.

FIG. 3 illustrates an embodiment of a pain management system andportions of an environment in which the system operates.

FIG. 4 illustrates an embodiment of a method for pain management such asmay be performed by the pain management system of FIG. 3.

FIG. 5 illustrates another embodiment of a pain management system andportions of an environment in which the system operates.

FIG. 6 illustrates an embodiment of a method for pain management such asmay be performed by the pain management system of FIG. 5.

FIG. 7 illustrates an embodiment of an implantable medical device of apain management system such as the pain management system of FIG. 5.

FIG. 8 illustrates an embodiment of an external device of a painmanagement system such as the pain management system of FIG. 5.

FIG. 9 illustrates an embodiment of a remote device of a pain managementsystem such as the pain management system of FIG. 5.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings which form a part hereof, and in which is shown byway of illustration specific embodiments in which the invention may bepracticed. These embodiments are described in sufficient detail toenable those skilled in the art to practice the invention, and it is tobe understood that the embodiments may be combined, or that otherembodiments may be utilized and that structural, logical and electricalchanges may be made without departing from the spirit and scope of thepresent invention. References to “an”, “one”, or “various” embodimentsin this disclosure are not necessarily to the same embodiment, and suchreferences contemplate more than one embodiment. The following detaileddescription provides examples, and the scope of the present invention isdefined by the appended claims and their legal equivalents.

This document discusses a pain management system that provides aquantitative measure of a patient's pain (or pain-related condition orsymptom) for diagnostic, monitoring, and/or therapeutic purposes. TheInternational Association for the Study of Pain (IASP, Washington, D.C.,U.S.A.) defines pain as an “unpleasant sensory and emotional experiencethat is associated with the actual or potential tissue damage ordescribed in such terms.” While also experienced by healthy people,elevated levels of pain are experienced by many patients suffering fromvarious types of injuries and diseases. Managing pain is a top priorityof physicians and nurses. In a clinic, pain is often quantified byquestioning the patient using the visual analog scale (VAS) or numericrating scale (NRS). VAS allows the patient to indicate a pointrepresenting the perceived pain level in a continuum from no pain to theworst imaginable pain. NRS allows to patient to select a number between0 and 10 representing the perceived pain level from no pain (“0”) to theworst imaginable pain (“10”). However, the pain value as indicated bythe patient is a subjective measure. One patient's “10” could be anotherpatient's “1”. In addition, monitoring and quantifying chronic painpresents additional challenges as the patient's perception of pain canchange over time. Furthermore, some patients such as infants anddisabled may have a challenge communicating their perception of pain. Alack of an objective measure of pain results in many challenges inhealthcare besides such examples.

The subjective pain value can lead to challenges such as over and underdosing of analgesics (especially opioids), misdiagnosis, suboptimaltherapy, extended hospital stay, and increased healthcare cost. Patientsand their care providers can both benefit from a more objective measureof pain. Many measureable parameters are known to relate to pain (seeTable1). Such parameters, individually or in combination, may bemeasured in the present pain management system discussed in thisdocument. In various embodiments, one or more of such parameters can beacquired to produce a pain score being a quantitative measure of pain.In various embodiments, this pain score can be used to adjust oroptimize a pain relief therapy in a closed-loop pain management system.For example, a pain monitoring system producing such a pain score can beintegrated into a closed-loop pain management system to titrate a paincontrol therapy. Examples of such pain control therapy can include anyone or any combination of spinal cord stimulation (SCS), dorsal rootganglia (DRG) stimulation, deep brain stimulation (DBS), motor cortexstimulation (MCS), transcranial direct current stimulation (tDCS),transcutaneous spinal direct current stimulation (tsDCS), trigeminalnerve stimulation, occipital nerve stimulation, vagus nerve stimulation(VNS), sacral nerve stimulation, pudendal nerve stimulation,sphenopalatine ganglion stimulation, sympathetic nerve modulation,multifidus muscle stimulation, adrenal gland modulation, carotidbaroreceptor stimulation, transcutaneous electrical nerve stimulation(TENS), transcranial magnetic stimulation (TMS), tibial nervestimulation, transcranial magnetic stimulation (TMS), radiofrequencyablation (RFA), pulsed radiofrequency ablation, ultrasound therapy,high-intensity focused ultrasound (HIFU), optical stimulation,optogenetic therapy, magnetic stimulation, other peripheral tissuestimulation therapies, other peripheral tissue denervation therapies,drug therapy (such as delivered from a drug pump), and nerve blocks orinjections (such as pharmaceuticals or biologics).

Pain alters various physiological and functional signals that can besensed from the patient invasively or non-invasively. Such signals canbe used to quantify the patient's pain levels. Physiological signalssuch as heart rate, blood pressure, respiration rate, and skinconductance, as well as signals derived from these such as heart ratevariability, may show abnormal patterns when the patient experiencespain, due to the patient's sympathetic activity elevated by pain. Thephysiological signals indicative of level of sympathetic activity cantherefore be collected via invasive and/or non-invasive means foranalysis of the patient pain state. Pain is felt by the patient throughtransmission of neural signals in the patient's nervous system. Thus,pain can be measured more directly by sensing the patient's neuralactivities. Pain alters neuronal connection, resulting in predictablechanges in electrical activity in the nervous system that can becaptured by, for example, electroencephalography (EEG) andelectromyography (EMG), which can be analyzed to assess the patient'spain by evaluating neural function. Functional signals such as thoseindicative of a measure of movement (e.g., activity level, gait pattern,range of motion, or sleep) or posture can also indicate the patient'spain state, because pain can impact various functional aspects of thepatient's daily activities when the patient has to compensate fordiscomfort during the activities. For example, the patient may try toreduce pain with irregular gait patterns and/or lower activity levels.Such functional signals can also be monitored for analyzing the patientpain state. In various embodiments, such physiological and functionalparameters when used individually or in various combinations can providefor an objective and quantitative measure of the patient's pain.

In addition to the physiological and/or functional parameters, theanalysis of pain can also include subjective input from the patient. Forexample, the patient's mood and mental state such as stress level andsleep quality can impact the patient's perception of pain. Furthermore,the analysis of pain can also include environmental parameters such astemperature, humidity, and/or air pressure, which may influencediscernment of pain. Time of day, which may capture circadian influenceon pain, can also be included in the analysis of pain.

In various embodiments, the present pain management system can sensepain-indicating physiological and functional signals and analyze thesignals using an objective method to produce a quantitative measurerepresentative of the pain state of the patient, to control therapydelivery, and to evaluate efficacy of therapeutic intervention for pain.In various embodiments, outcomes of the analysis can include anobjective pain measure based on one or more physiological parameters andone or more function parameter. In various embodiments, the objectivepain measure is further combined with relevant medical history of thepatient and/or input received from the patient or their caregivers toproduce a composite pain score. This pain score represents the patient'spain intensity and can be reported to the patient and/or a careprovider, and can be used to start, stop, and adjust pain managementtherapies.

While various physiological or functional parameters have been studiedfor indicating or measuring pain, the present pain management systemcombines both physiological and functional parameters to better capturethe patient's pain experience and quantify the pain experience into anobjective pain value (e.g., the composite pain score). For example, thesystem can include sensors for sensing the physiological and functionalsignals, a patient information input to receive patient information suchas subjective pain level perceived by the patient and/or pain-relatedinformation in the patient's medical history, a processing circuit toproduce the physiological and functional parameters by extractingrelevant information from the sensed signals and computing the compositepain score based on the physiological and functional parameters and thepatient information. The composite pain score as well as the algorithmfor its computation can be updated continuously, periodically, accordingto other schedules, or as needed to reflect the changes in thephysiological and functional parameters and the patient information. Thecomposite pain score can be used for monitoring the patient's pain stateand/or titrating one or more pain relief therapies the patient receives.

FIG. 1 illustrates an embodiment of a pain analyzer 100 that can includea parameter analyzer 102 and a pain score generator 104. In theillustrated embodiment, parameter analyzer 102 receives and analyzes oneor more physiological parameters each indicative of a physiologicalfunction or state of a patient, one or more functional parameters eachindicative of a physical activity or state of the patient, and one ormore patient parameters related to the pain, such as a parameterrepresentative of intensity of the pain specified by the patient. Painscore generator 104 computes a composite pain score using an outcome ofthe analysis. The composite pain score indicates a degree of the pain.In various embodiments, parameter analyzer 102 can receive and analyzeat least one physiological parameter and one functional parameter. Painscore generator 104 can compute a composite pain score using an outcomeof the analysis.

In various embodiments, parameter analyzer 102 can produce a signalmetric using one or more physiological parameters, one or morefunctional parameters, and/or the one or more patient parameters. In oneembodiment, parameter analyzer 102 produces the signal metric using atleast one parameter selected from the one or more physiologicalparameters, the one or more functional parameters, or the one or morepatient parameters. In one embodiment, parameter analyzer 102 producesthe signal metric using at least two parameters selected from the one ormore physiological parameters, the one or more functional parameters, orthe one or more patient parameters. In one embodiment, parameteranalyzer 102 produces the signal metric using at least one physiologicalparameter and one functional parameter. In one embodiment, parameteranalyzer 102 produces the signal metric using at least two parametersselected from a physiological parameter, a functional parameter, and apatient parameter. In one embodiment, parameter analyzer 102 producesthe signal metric using the one or more physiological parameters and theone or more functional parameters. In one embodiment, parameter analyzer102 produces the signal metric using the one or more physiologicalparameters and the one or more patient parameters. In one embodiment,parameter analyzer 102 produces the signal metric using the one or morefunctional parameters and the one or more patient parameters. In oneembodiment, parameter analyzer 102 produces the signal metric using theone or more physiological parameters, the one or more functionalparameters, and the one or more patient parameters.

The signal metric can be a linear or nonlinear combination of the one ormore physiological parameters, the one or more functional parameters,and/or the one or more patient parameters. In various embodiments,parameter analyzer 102 can produce the signal metric using the one ormore physiological parameters, the one or more functional parameters,and/or the one or more patient parameters with the weighting factorseach applied to one of these parameters. In various embodiments,parameter analyzer 102 can adjust the weighting factors throughautomatic learning and adaptation to the patient over time (e.g., basedon stored parameters and/or outcomes of analysis, such as featuresextracted from the parameters). In various other embodiments, parameteranalyzer 102 can allow the weighting factors to be adjusted manually. Invarious other embodiments, the weighting factors can be adjustedaccording to a calibration schedule or as needed, and the adjustment canbe performed by a user such as a physician or other authorized careprovider in a clinic, or initiated by the patient and performed byparameter analyzer 102 automatically at home. In various embodiments,the weighting factors can be patient-specific and dynamically changedbased on the patient's conditions and/or activities, such as source ofpain, type of pain, related pathological condition, physical condition(e.g., bed-ridden), time of day, and/or physical activity (e.g., patientbeing sleeping or walking).

In various embodiments, pain score generator 104 can compute thecomposite pain score using the signal metric. In one embodiment, painscore generator 104 trends the signal metric and computes the compositepain score based on the resulting trending of the signal metric.

FIG. 2 illustrates an embodiment of a pain monitoring circuit 210. Inthe illustrated embodiment, pain monitoring circuit 210 includes one ormore physiological signal sensors 212, a physiological signal sensingcircuit 214, a physiological parameter generator 216, one or morefunctional signal sensors 218, a functional signal sensing circuit 220,a functional parameter generator 222, a patient information input device224, a patient information processing circuit 226, a patient parametergenerator 228, and pain analyzer 100. In various embodiments, painmonitoring circuit 210 can include at least one or more physiologicalsignal sensors 212, physiological signal sensing circuit 214,physiological parameter generator 216, one or more functional signalsensors 218, functional signal sensing circuit 220, functional parametergenerator 222, and pain analyzer 100.

In various embodiments, one or more physiological signal sensors 212 caneach sense one or more physiological signals, and can each be anon-invasive, percutaneous, or implantable sensor. Physiological signalsensing circuit 214 can process the one or more physiological signals.Physiological parameter generator 216 can generate the one or morephysiological parameters using the processed one or more physiologicalsignals. Examples of the one or more physiological parameters caninclude one or more measures of physiologic manifestations of change inthe patient's sympathetic activity (referred to as “autonomicmeasures”), one or more direct measures of neuronal activity (referredto as “neuron/brain measures”), and/or one or more chemical or analyteparameters derived from body tissue, fluid, and/or excretion collectedfrom the patient.

Examples of the one or more autonomic measures can include (1) heartrate and heart rate variability, including time and frequency domainmeasures, statistic metrics in the time domain including standarddeviation of the baseline normal R-R intervals to assess changes frombaseline, the square root of mean squared differences of successive R-Rintervals over different time windows, q-factors for spectral peaks atvery low frequency (VLF), low frequency (LF), and high frequencies (HF),ratio of power in the different frequency bands (LF/HF), changes infrequency of maximum peaks over time, and complexity metrics derivedfrom these signals; (2) blood pressure measures including systolic anddiastolic blood pressure, pulse transit time, wave amplitude, and volume(the blood pressure measures can be obtained using heart sounds such asby leveraging the second heart sound (S2) as a strong surrogate forpressure readings through either invasive or noninvasive means, or canalso be acquired using blood pressure cuffs or photoplethysmograms(PPGs)); and (3) galvanic skin response, including time and frequencydomain measures. Additional examples of the one or more autonomicmeasures can be found in Table 1 (e.g., under “Autonomic Measures”).Examples of the neuron/brain measures can include (1)electroencephalogram (EEG) based pattern analysis and frequency domainmeasures; (2) electromyogram (EMG) based time (amplitude and latency)and frequency domain measures; and (3) response to specific evokedpotentials (EPs) that are affected under cognitive tasks, mental statechanges, mood variation, presence of depression, and/or presence ofdifferent levels of pain. Additional examples of the one or moreneuron/brain measures can be found in Table 1 (e.g., under “Neuron/BrainMeasures”). In various embodiments, physiological parameter generator216 can generate any one or any combination of these examples as the oneor more physiological parameters. Examples of the one or more chemicalor analyte parameters can include parameters derived from the patient'sblood, sweat, saliva, breath, tissue, etc. Additional examples one ormore chemical or analyte parameters can be found in Table 1 (e.g., under“Biochemical Measures”).

In various embodiments, one or more functional signal sensors 218 cansense one or more functional signals, and can each be a non-invasive,percutaneous, or implantable sensor. Functional signal sensing circuit220 can process the one or more functional signals. Functional parametergenerator 222 can generate the one or more functional parameters usingthe processed one or more functional signals. Examples of the one ormore functional signals can include measures of (1) movement (e.g.,activity level, gait pattern, range of motion, or sleep) and (2)posture. Additional examples of the one or more functional parameterscan be found in Table 1 (e.g., under “Functional Measures”). In variousembodiments, physiological parameter generator 222 can generate any oneor any combination of these examples as the one or more functionalparameters.

In various embodiments, patient information input device 224 can receivepatient information related to pain. Patient information processingcircuit 226 can process the patient information. Patient parametergenerator 228 can generate one or more patient parameters using theprocessed patient information. Examples of the one or more patientparameters can (1) parameters derived from input from the patient suchas perceived pain levels, mood, and stress levels (including externalinteractions, such as interactions with another person) as a way toquantify non-physical activity); and (2) parameters derived from thepatient's medical history record (e.g., demographic data, diagnoses,procedures applied, and prescriptions). Some additional examples of theparameters derived from the patient's medical history record can befound in Table 1 (e.g., under “Biochemical Measures”). In variousembodiments, patient parameter generator 228 can generate any one or anycombination of these examples as the one or more patient parameters.

FIG. 3 illustrates an embodiment of a pain management system 330 andportions of an environment in which system 330 operates. System 330 caninclude sensors 332, a portable device 334, a network 338communicatively coupled to portable device 334 via a communication link336, and a medical facility 340 communicatively coupled to network 338.A pain monitoring circuit such as pain monitoring circuit 210 can bedistributed in sensors 332 and portable device 334. In variousembodiments, portable device 334 can be implemented as a dedicateddevice or in a generic device such as a smartphone, a laptop computer,or a tablet computer.

For example, sensors 332 may include at least one sensor ofphysiological sensor(s) 212 and one sensor of functional signalsensor(s) 218, and portable device 334 can include the remainingcomponents of pain monitoring circuit 210. The composite pain score aswell as other data acquired by portable device 334 can be transmitted tonetwork 338 via communication link 336 to be stored, further analyzed,and/or inform the patient's healthcare provider. When the composite painscore and/or the other data indicate that the patient needs medicalattention, a notification will be transmitted to medical facility 340from network 338. In various embodiments, sensor(s) 332 can includeexternal, percutaneous, and/or implantable sensors that communicate withportable device 334 via wired and/or wireless links, and communicationlink 336 can be a wired or wireless link.

FIG. 4 illustrates an embodiment of a method 400 for pain management. Inone embodiment, system 330 is configured to perform method 400 for apatent.

At 402, one or more physiological parameters and one or more functionalparameters are generated. The one or more physiological parameters areeach indicative of a physiological function or state of the patient. Theone or more functional parameters are each indicative of a physicalactivity or state of the patient. Examples of such one or morephysiological parameters can include the physiological parameters thatcan be generated by physiological parameter generator 216 as discussedabove with reference to FIG. 2 and Table 1. Examples of such one or morefunctional parameters can include the functional parameters that can begenerated by functional parameter generator 222 as discussed above withreference to FIG. 2 and Table 1.

Optionally at 404, patient input is received. Optionally at 406, patienthistory is received. The received patient input and/or patient historyinclude one or more patient parameters related to the pain of thepatient. Examples of such one or more patient parameters can include thepatient parameters that can be generated by patient parameter generator228 as discussed above with reference to FIG. 2 and Table 1. In variousembodiments, the one or more patient parameters can include one or moreparameters directly entered by the patient or another person attendingthe patient as well as one or more parameters derived from informationentered by the patient or another person attending the patient and thepatient's medical history. In one embodiment, the one or more patientparameters includes a parameter representative of intensity of the painspecified by the patient based on his or her perception of the pain.

At 408, the parameters generated and/or received at 402, 404, and 406are analyzed. In various embodiments, the analysis can result in asignal metric using one or more physiological parameters, one or morefunctional parameters, and/or the one or more patient parameters. In oneembodiment, the analysis results in the signal metric using at least oneparameter selected from the one or more physiological parameters, theone or more functional parameters, or the one or more patientparameters. In one embodiment, the analysis results in the signal metricusing at least two parameters selected from the one or morephysiological parameters, the one or more functional parameters, or theone or more patient parameters. In one embodiment, the analysis resultsin the signal metric using at least one physiological parameter and onefunctional parameter. In one embodiment, the analysis results in thesignal metric using at least two parameters selected from aphysiological parameter, a functional parameter, and a patientparameter. In one embodiment, the analysis results in the signal metricusing the one or more physiological parameters and the one or morefunctional parameters. In one embodiment, the analysis results in thesignal metric using the one or more physiological parameters and the oneor more patient parameters. In one embodiment, the analysis results inproduces the signal metric using the one or more functional parametersand the one or more patient parameters. In one embodiment, the analysisresults in produces the signal metric using the one or morephysiological parameters, the one or more functional parameters, and theone or more patient parameters.

In various embodiments, weighting factors can be generated, and thesignal metric can be produced using the one or more physiologicalparameters, the one or more functional parameters, and/or the one ormore patient parameters with the weighting factors each applied to oneof these parameters. In another embodiment, one or more of the one ormore physiological parameters, the one or more functional parameters,and the one or more patient parameters are preprocessed to extractrelevant pain information features before generating the weightingfactors to be applied to these features. In another embodiment, theweighting factors are generated using one or more machine learningtechniques such as neural network, fuzzy logic, support vector machines,and/or generalized linear or non-linear regressions.

At 410, a composite pain score is computed. In various embodiments, thecomposite pain score can be computed using the signal metric. In variousembodiments, additional parameters such as environmental parameters andtime can be used in computing the composite pain score, such as byincluding in the analysis that results in the signal metric. Theenvironmental parameters, such as temperature, humidity, and/or airpressure, may influence discernment of pain. In various embodiments,such environmental parameters can be measured by system 300 and/orobtained from weather forecasts based on location (e.g., specifiedmanually or using a global positioning system) to anticipate or predicttheir impact to the composite pain score. One or more weighting factorscan be determined based on the reliability of these environmentalparameters (e.g., depending on how they are obtained) and applied incomputing the composite pain score. Time of day may capture circadianinfluence on pain. There are still additional parameters that can affectpain, and can be used in computing the composite pain score, such as byincluding in the analysis that results in the signal metric. Examplescan include, but are not limited to, amount and/or quality of sleep(e.g., as measured by system 330), amount and/or type of activity duringa preceding period of time (e.g., the previous day or week, and measuredby system 330), personal events that may have positive impact ornegative impact on pain, medication changes, time of year (e.g.,birthday and holidays), personal events that may have positive impact ornegative impact on pain (e.g., church and socialization activitiesmaking for consistent good moods on Sunday with a let down on Monday, asmonitored and recognized as a pattern by system 330), and/or deviationfrom patterns determined by system 330 (e.g., regular activity aroundlunch time because walking to a cafeteria stops due to changes in painperception not identified by other parameters). In one embodiment, thesignal metric is trended, and the composite pain score is computed basedon the trend.

At 412, the algorithm used to compute the composite pain score iscalibrated. In various embodiments, the calibration can includeadjusting the one or more weighting factors manually, automatically bylearning and adapting to the patient's circumstances and conditions overtime, and/or adjusting the weighting factors based on changes in thephysiological and functional parameters. The weighting factors can beadjusted according to a calibration schedule or as needed. In variousembodiments, the calibration can be a continuous process. For example,calibration can be performed over the course of minutes or longer, e.g.,days, to encompass a range of activities. Calibration can be a promptedactivity or scheduled to occur intermittently, for example. Differentweighting factors can be used for various activities, such as sleepingand walking. In various embodiments, the weighting factor can be linearor non-linear in nature.

At 414, whether medical intervention is required is determined, such asby comparing the composite pain score to one or more thresholds. Ifintervention is not required as determined at 414, the one or morephysiological parameters and one or more functional parameters aregenerated again (i.e., their values are updated) for continuedmonitoring of the patient.

At 416, the result of the computation, including at least the compositepain score, is displayed to the patient or a caregiver. At 418, ifintervention is required as determined at 414, relevant medicalpersonnel is notified for appropriate action that can be dependent onthe composite pain score. Examples of the appropriate action can includeinstructing the patient to take medication, instructing the patient tovisit a clinic, or sending medical personnel to visit the patient.

FIG. 5 illustrates another embodiment of a pain management system 530and portions of an environment in which system 530 operates. System 530can include an implantable medical device 542, a portable device 534communicatively coupled to implantable medical device 542 via a wirelesscommunication link 544, network 338 communicatively coupled to portabledevice 534 via communication link 336, and medical facility 340communicatively coupled to network 338. A pain monitoring circuit suchas pain monitoring circuit 210 can be distributed in implantable medicaldevice 542 and portable device 534, and implantable medical device 542can deliver one or more pain relief therapies. In various embodiments,portable device 534 can be implemented as a dedicated device or in ageneric device such as a smartphone, a laptop computer, or a tabletcomputer.

For example, implantable medical device 542 may include at least onesensor of physiological sensor(s) 212 and one sensor of functionalsignal sensor(s) 218, and portable device 534 can include the remainingcomponents of pain monitoring circuit 210. The composite pain score aswell as other data acquired by portable device 534 can be transmitted tonetwork 338 via communication link 336 to be stored, further analyzed,inform the patient's healthcare provider, and/or used to controldelivery of one or more pain relief therapies from implantable medicaldevice 542. When the composite pain score and/or the other data indicatethat the patient needs medical attention, such as when system 530 isunable to automatically adjust the one or more pain relief therapies fora satisfactory result as indicated by the composite pain score, anotification will be transmitted to medical facility 340 from network338.

FIG. 6 illustrates an embodiment of a method 600 for pain management. Inone embodiment, system 530 is configured to perform method 600 for apatent. Method 600 can be performed for monitoring pain of the patientand delivering one or more pain relief therapies to the patient withclosed-loop control. As illustrated in FIG. 6, method 600 includes steps402, 404, 406, 408, 410, and 412 of method 400.

At 614, the composite pain score is compared to a therapy thresholdindicating a need for adjusting a pain relief therapy. If the compositepain score does not exceed the therapy threshold as determined at 614,the one or more physiological parameters and one or more functionalparameters are generated again (i.e., their values are updated) forcontinued monitoring of the patient. Examples of the pain relief therapycan include neuromodulation therapies (e.g., SCS, PNS, DBS, and TMS) anddrug therapies.

At 616, when the composite pain score exceeds the therapy threshold asdetermined at 614, the pain relief therapy is adjusted. The adjustmentcan include starting a therapy, increasing intensity (e.g.,neurostimulation energy or drug dose), switching to a different typetherapy, or adjusting any therapy parameters. Examples of therapyparameters for various types of neuromodulation therapies can includepulse frequency, burst frequency, pulse width, waveform shape,anode/cathode configurations, and current fractionalization.

At 618, whether the composite pain score exceeds a notificationthreshold is determined. At 620, if the pain exceeds the notificationthreshold as determined at 618, relevant medical personnel is notifiedfor appropriate action that may be dependent on the composite pain scoreand/or the record of delivery of the pain relief therapy. Examples ofthe appropriate action can include instructing the patient to takemedication, instructing the patient to visit a clinic, or sendingmedical personnel to visit the patient. If the pain does not exceed, thenotification threshold as determined at 618, no notification to relevantmedical personnel is necessary. In any case, the one or morephysiological parameters and one or more functional parameters arecontinued to be generated (i.e., their values are updated) for continuedassessment of the patient pain level.

FIG. 7 illustrates an embodiment of an implantable medical device 742,which represents an example of implantable medical device 542.Implantable medical device 742 can include a pain monitoring circuit710, an implant communication circuit 752, and a pain relief device 754.Pain monitoring circuit 710 represents an example of pain monitoringcircuit 210 as implemented in an implantable medical device. When theone or more patient parameters are used by pain analyzer 100, patientinformation input device 224 can receive the patient information from anexternal device communicatively coupled to implantable medical device742 via communication link 544.

Implant control circuit 746 controls the operation of implantablemedical device 742 and can include a communication controller 748 and atherapy controller 750. Communication controller 748 can controltransmission of the composite pain score the external device, such as ona periodical basis or according to another specified schedule, when thecomposite pain score exceeds a specified threshold, when change in thecomposite pain score exceeds a specified threshold, or when the rate ofchange in the composite pain score exceeds a specified threshold.Therapy controller 750 can control the delivery of the one or morepain-relief therapies using the composite pain score and therapyparameters. Implant communication circuit 752 allow implantable medicaldevice 742 to communicate with the external device via communicationlink 544. Pain relief device 754 can deliver one or more pain-relieftherapies. In various embodiments, pain relief device 754 can include aneuromodulator to deliver electrical stimulation (such as SCS, PNS, DBS,and/or TMS) and/or a drug pump to deliver one or more pain suppressionagents.

FIG. 8 illustrates an embodiment of an external device 834, such as maybe implemented in portable device 534. External device 834 can includean external user interface 856, an external control circuit 862, and anexternal communication circuit 868. In various embodiments, externaldevice 834 can be implemented in a portable device such as a hand-heldor wearable device.

External user interface 856 can include a user input device 858 and apresentation device 860. User input device 858 can receive patientinformation such as a subjective input from the patient to indicate thedegree of the pain as perceived by the patient. Presentation device 860can include a display screen and/or other audio and/or visualpresentation devices. In one embodiment, a touchscreen is used as userinput device 858 and presentation device 860. External control circuit862 controls operation of external device 834 and can include anotification controller 864 and a therapy controller 866. Notificationcontroller 864 can receive the composite pain score from implantablemedical device 742, produce a notification using the composite painscore, determine one or more recipients of the notification using thecomposite pain score, and control delivery of the notification to eachof the one or more recipients. The recipients can include the patientand/or various users of a pain management system such as system 530. Invarious embodiments, notification controller 864 can present thenotification using presentation device 860. The notification can includethe composite pain score, one or more indicators representing the painscore, an alert or alarm message regarding the patient's pain state,and/or instructions for actions to be taken by the patient. In variousembodiments, notification controller 864 can produce and present thenotification when the composite pain score exceeds a specifiedthreshold, when change in the composite pain score exceeds a specifiedthreshold, or when the rate of change in the composite pain scoreexceeds a specified threshold. Therapy controller 866 can produceexternal commands for adjusting the therapy parameters using thecomposite pain score and the patient information and transmit theexternal commands to implantable medical device 742 via communicationlink 544. External communication circuit 868 allow external device 834to communicate with implantable medical device 742 via communicationlink 544 and to communicate with a remote device via communication link336.

FIG. 9 illustrates an embodiment of a remote device 970, such as may beimplemented in network 338 and/or medical facility 340. Remote device970 can be used for patient monitoring and therapy control, and caninclude a remote user interface 972, a remote control circuit 978, and aremote communication circuit 984.

Remote user interface 972 can include a user input device 974 and apresentation device 976. User input device 974 can receive patientinformation such as patient history stored in network 338 and/or medialfacility 340, and can also receive user commands for adjusting the oneor more pain-relief therapies. Such user command may be determined basedon updated knowledge about the patient's conditions and/or results ofone or more pain-relief therapies received by the patient. Presentationdevice 976 can include a display screen and/or other audio and/or visualpresentation devices. In one embodiment, a touchscreen is used as userinput device 974 and presentation device 976. Remote control circuit 978can include a notification controller 980 and a therapy controller 982.Notification controller 980 can receive the notification transmittedfrom external device 834, determine one or more further recipients ofthe notification, and control delivery of the notification to each ofthe one or more further recipients. Such further recipients can includephysicians and/or other caregivers attending the patient, a hospital,and a medical emergency response facility. Therapy controller 982 canproduce remote commands for adjusting the delivery of the one or morepain-relief therapies using the notification and the user commands. Invarious embodiments, therapy controller 866 of external device 834 canproduce the external commands using the composite pain score, thepatient information, and the remote commands. Remote communicationcircuit 984 can communicate with external device 834 via communication336 and network 338.

In various embodiments, circuits of the present pain management system,including its various embodiments discussed in this document, may beimplemented using a combination of hardware and software. For example,the circuits may be implemented using an application-specific circuitconstructed to perform one or more particular functions or ageneral-purpose circuit programmed to perform such function(s). Such ageneral-purpose circuit includes, but is not limited to, amicroprocessor or a portion thereof, a microcontroller or portionsthereof, and a programmable logic circuit or a portion thereof.

It is to be understood that the above detailed description is intendedto be illustrative, and not restrictive. Other embodiments will beapparent to those of skill in the art upon reading and understanding theabove description. The scope of the invention should, therefore, bedetermined with reference to the appended claims, along with the fullscope of equivalents to which such claims are entitled.

TABLE 1 Parameters indicative of level of pain. Bio-marker SignalsSensed (Parameter) Physiology/Definition (Examples only) ReferencesAutonomic Measures Heart Rate (HR) Indicator of sympathetic tone. ECG,PPG 1, 2 Higher HR indicates higher sympathetic nervous activity (SNA)Heart Rate Measure of autonomic balance. ECG, PPG- 3, 4, 5, 6, 7,Variability (HRV) Autonomic dysfunction at the base 8, 9, 10 of manydisease states. Appears to be a reliable marker for adaptive stress,including both dynamic and cumulative load. Acute stress and chronicstress both lower HRV AVNN Average of all NN intervals ECG, PPG SDINTNTStandard deviation of all NN ECG, PPG intervals (Measure of long termHRV) SDANN Standard deviation of the averages ECG, PPG of NN intervalsin all 5-minute segments of a 24-hour recording (Measure of long termHRV) SDNNIDX Mean of the standard deviations of ECG, PPG NN intervals inall 5-minute segments of a 24-hour recording RMSSD Square root of themean of the ECG, PPG squares of differences between adjacent NNintervals. (Measure of short term HRV) pNN50 Percentage of differencesbetween ECG, PPG adjacent NN intervals that are greater than 50 ms. vLFTotal spectral power of all NN ECG, PPG intervals between 0.003 and 0.04Hz LF Total spectral power of all NN ECG, PPG intervals between 0.04 and0.15 Hz HF Total spectral power of all NN ECG, PPG intervals between0.15 and 0.4 Hz LF/HF Ratio of low to high frequency ECG, PPG powertotal power total spectral power of al NN ECG, PPG intervals up to 0.4Hz UsEn Ultra-short entropy (UsEn) is a ECG, PPG nonlinear approach thatis thought to offer an insight into the overall structure of the RRregulatory system with a connection between disorder and a decrease inentropy alpha 1 Short term fractal scaling exponent ECG, PPG measuresthe qualitative characteristics and correlation features of HR behavior.Galvanic Skin SNA causes sweat glands to fill up Electrodes on 11, 12,13, 14 Response (GSR) and skin conductance increases the hand, creatingskin conductance measure fluctuations. conductivity Photo- Reduction inthe amplitude of PPG PPG 15, 16, 17, 18 Plethysmographic is caused byperipheral (PPG) vasoconstriction and the nociception response duringgeneral anesthesia. Vasoconstriction as a result of increased SNA. PulseRate Could be a replacement measure PPG 19, 20, 21 Variability (PRV) forHRV. Can be used to estimate HRV at rest. Blood Pressure Marker ofsympathetic ton. PPG 22, 23 24, 25 (BP) Increased ton causesvasoconstriction and thus elevated BP. Increased BP is associated withincreased pain levels Pulse Transit Time Vasoconstriction is aphysiological PPG, possible 26, 27, 28 & Pulse Wave response to painwhich directly internal sensor Amplitude impacts the pulse transit timeand (at 2 locations to (Alternative pulse wave amplitude. In the measuretransit measure for BP) presence of painful stimuli, both time) pulsetransit time and pulse wave amplitude decrease. Respiration Rate Measureof sympathetic tone. ECG, embedded 29, 30, 31, (RR) Elevated respiratoryrate strain gauge corresponds to increased pain. Pupil Diameter Dilationof the pupil is indicative of *Imaging 32 sympathetic activationRespiratory Sinus RSA is a physiological indicator 33, 34, 35,Arrhythmia (RSA) that may have implications for 36, 37 responses to painand stress. It is essentially the transfer function from respirationrate to R-R intervals. Another way to assess cardiac autonomic function.Pain is associated with an impairment of neurocardiac integrity whichcan be measured through RSA which decreases in the presence of increasedsympathetic activity / decreased parasympathetic activity. BaroreceptorIncreased baroreceptor response is BP monitoring 38, 39, 40, Sensitivityassociated with decreased pain 41, 42, 43, levels. 44, 45, 46, 47Normalized Pulse Sympathetic tone causes vascular Measured in the 48, 49Volume (NPV) constriction. This vascular tone can outer ear or at bemeasured in several locations on the finger tip the body to indicatesympathetic tone. NPV can be derived from the fingertip using PPG. Itcan also be derived from the bottom of the ear canal. FunctionalMeasures Activity Measuring activity in patients with Accelerometer 50,51, 52 pain can be an indicator of pain level with patients in severepain participating in less activity Timed up-and-go Faster up-and-gotime :shorter time Accelerometer to complete task), less discomfort andable to move more quickly. Physical activity Increased physical activityis a sign Accelerometer of decreased discomfort Gait Patients with painmay have altered Accelerometer 53, 54, 55, gait due to pain, such as alimp. gyroscope 56, 57, 58, Velocity set distance to walk divided bytime Accelerometer 59, 60, it takes to walk the set distance gyroscopeStride Length linear distance between the Accelerometer/ placement ofboth feet gyroscope Swing Time time from the moment the foot liftsAccelerometer/ from the floor until it touches again gyroscope SingleLimb time from when the heel touches Accelerometer/ Support Time theflood until toes are lifted gyroscope Gait autonomy maximum time aperson can walk, Accelerometer/ taking into account the number andgyroscope duration of stops Trunk-Pelvis Altered gait patterns areobserved Gyroscope Rotation, balance in patients with pain. Due topain/discomfort, the coordination of the trunk and pelvis rotations varyfrom healthy subjects. In a healthy person, pelvis-thorax coordinationin the transverse plane evolves gradually from in-phase coordinationtowards antiphase coordination with increasing walking velocity. Inpatients with pain these movements are more rigid and less flexiblecoordination. Facial expressions Particular facial expressions/cuesImaging 61 are associated with pain (Facial Action Units) such as nosewrinkling and cheek-raising Sleep Quality Poor sleep quality is oftenobserved accelerometer, 62, 63, 64, 65 when patients are in pain. Moresubjective movement and wakefulness during sleep. Quality of Quality oflife/mood can affect pain subjective 66 Life/Mood (Can be score. Bettermood can decrease subjective or pain perception/intensity objective)Stress - Subjective Stress levels can greatly affect ECG (HRV), 67, 68,measure HRV and sympathetic tone. subjective Neuron/Brain MeasuresQuantitative Method used to assess damage to Neurometer 69, 70, 71,Sensory Test (QST) the small nerve endings, which 72, 73, 74, detectchanges in temperature, and 75, 76 large nerve endings, which detectvibration Warm Heat stimuli, subject reports Neurometer temperaturechange or heat pain threshold Cold Cold stimuli, subject reportsNeurometer temperature change or cold pain threshold Vibration Measuresensation/sensitivity to Neurometer vibration. Set frequency and changeamplitude to detect threshold/sensitivity Current Perception Also knownas sensory nerve Neurometer Threshold (CPT) conduction thresholdtesting. Entails the quantification of the sensory threshold totranscutaneous electrical stimulation. CPT measure represents theminimal amount of painless, neuroselective transcutaneous electricalstimulus required to reproducibly evoke a sensation. Pain Perception PPTrepresents the minimum Neurometer Threshold (PPT) current intensity thatproduced pain Pain Tolerance PTT measure is the maximum NeurometerThreshold (PTT) amount of neuroselective electrical stimulus that asubject can tolerate Tactile Stimulation of the index finger withNeurometer Discrimination assessments of 2-point Thresholddiscrimination thresholds as a marker for tactile perception. EEGIncreased activity in the pain matrix EEG 77, 78, 79, 80 of patients ina high pain state versus low pain state Spectral Power Increasedspectral power is EEG attributable to theta over activity. DominantIncreased peak height and EEG Frequency (DF) decreased DF due to slowedrhythmicity in EEG in neuropathic pain. (Contact) Heat EPs Uses rapidlydelivered heat pulses EEG 81, 82, 83, 84 with adjustable peaktemperatures to stimulate the differential heat/warm thresholds ofreceptors expressed by the A-delta and C. Believed to be composed of atleast 2 overlapping components. Some theorize that it reflects thedegree of discomfort or unpleasantness thus reflecting the emotional-motivational aspect Provides a useful neurophysiologic tool for studyingthe emotions associated with pain Somatosensory EPs Electrical signal isnervous system EEG in response to a sensory stimuli. Consists of aseries of waves that reflect sequential activation of neural structuresalong somatosensory pathways EMG Reflect endogenous processing of EMGpain information in response to external stimuli. Neurophysical testP40-SEP amplitude, H-reflex EMG, Reporter 85 amplitude, Rill reflexthreshold, EMG-EP and RIII reflex area. Neurophysical machine testsdetect and record the electrical potential generated by muscle cellswhen they are activated. These signals can be analyzed to detect medicalabnormalities or to analyze the biomechanics of movement. SpinalStability, EMG activity is elevated in low EMG, sEMG 86, 87, 88, LumbarEMG back pain patients especially during (surface EMG) 89, 90, 91, 92dynamic movements. This increased could be due to restricted range ofmotion and/or a compensatory mechanism to maintain stability. It iswidely accepted that there is a relationship between pain, stiffness,and muscle activity in low back pain patients. Nociceptive Nociceptiveflexion reflex (NM.) is sEMG on the 93, 94, 95, Flexion Reflex / aphysiological, polysynaptic reflex bicep femoris 96, 97 Nociceptiveallowing for painful stimuli to muscle Withdrawal Reflex activate anappropriate withdrawal response. To capture this response, the suralnerve is stimulated and the EMG response is recorded at the bicepfemoris muscle. This stimulation elicits 2 reflex responses: (1) RIIreflex which has a short latency, low activation threshold, and is atactile reflex and (2) RIII reflex which has a longer latency, higheractivation threshold, and is the nociceptive reflex. RIII is the focusof the NFR correlations with pain. The measured parameter is the NTRthreshold (amplitude of stimulation necessary to activate RIII) foractivation, which has shown to directly correlate to perceived pain.MSNA Muscle sympathetic nerve activity. EMG 98, 99, 100, 101 Variance inMSNA may be associated with cardiac output with a negative relationshipobserved between MSNA and cardiac output. MSNA can influence FIRV. MSNAcould be used as an indicator of autonomic activity. Default-ModeProposed theory is that long-term EEG, fMRI 102, 103 Network (DMN) painalters the functional connectivity of cortical regions known to beactive at rest. In chronic pain patients, these regions are associatedwith more activity, unable to deactivate. Gray Matter Pain can lead tolong term changes MRI 104 105 Volume in the brain including changes inthe volume of gray matter. GMV changes are region dependent. Changesseen are not necessarily in regions of the brain correlated with painMEG Theta Increased total power in the theta MEG 106, 107 Activity(Power) range (7-9Hz) is associated with increased pain state MRSpectroscopy MRS can be used to detect MR 108 Metabolites alterations inthe biochemistry in spectroscopy the brain associated with chronicpain - in regions associated with pain. Distinct patterns were observedbetween painful and painless states. Biochemical Measures CytokineProfile Increased pro-inflammatory Blood draw 109 cytokines anddecreased anti- inflammatory cytokines can increase pain/discomfort pro-TNFa - applied to peripheral nerve Blood draw inflammatory fibers invitro and in-vivo experiments leads to increased electrical activity inpatients with pain, Increased TNFa in the blood and thus endoneuralenvironment might also lead to increased C-fiber activity and sensationof pain. 1L-2 - has shown both analgesic and algetic effects. Elevatedlevels associated with pro-algetic effect. anti- IL-4, IL-10. Roles indown Blood draw inflammatory regulating the production of pro-inflammatory cytokines. Heightened 1L-4 & IL-10 protein may reflect anatural analgesic system regulating the activity and sensitivity of theendogenous opioid system. Biochemical Neurotensin, oxytocin and cortisolBlood draw 110, 111, Markers levels were increased after 112, 113intervention (cervical and spinal manipulation). This response occurredimmediately after intervention and the differences between theintervention and control groups were gone at 2 hours after interventionMDA (malondialdehyde) is a marker of oxidative stress and is increasedin pain states DMS (ditnethylsphingosine) is a small molecule byproductof cellular membranes in the nervous system. This study was perfortnedin rats where elevated levels of DMS were seen in rats with neuropathicpain. Biochemical mechanismsof chronic pain and fatigue. Chronic painsubjects had a reduction in serum sodium, increase in levels of markersof tissue damage (ALT (alanine aminotrasaminate) and AST (aspartateaminotranskrase)) and an increase in the tyrosine: leucine ratio whichrepresents alterations in protein turnover. Lactic acid andproteoglycans metabolic markers) GABA Evidence that (ABA transmission —114 is involved in the inhibition of dysesthesia, allodynia, and othersigns of neuropathic pain P2X4 Receptor After nerve injury P2X4receptors — 115 Expression Levels are upregulated in spinal microglia byseveral factors at the transcriptional and translational levels increaseHR and BP are associated with increased burst amplitude but not in allpatients. May have implications for individual differences in CVconsequences of CP. Salivary Levels of interleukin (1L)1a, IL8, Saliva116, 117 neuropeptide / AgRP, cortisol, monocyte cytokine / hormonechemotactic protein-1 (MCP1), detection dynorphin A, prolactin, valine,proline, hypoxanthine, propionate, formate, and acetate in salivasamples could be used to distinguish between patients with and withoutpain. Hypothalamic-pituitary-adrenal (HPA) axis, one of the main bodilystress systems, function has been found to be reduced in chronic painpatients. Salivary cortisol is commonly used to assess HPA axisfunction. Epinephrine and norepinephrine levels could potentially beused. glial cell-derived Concentrations of glial cell-derived CSF 119neurotrophic factor neurotrophic factor in cerebrospinal fluid (CSF)have been shown to be higher in neuropathic pain patients. NeuropeptideCSF levels of nociceptin/orphanin CSF 120 ligand: (N/OFQ) have beenfound to be nociceptin/orphanin lower in patients treated with (N/OFQ)morphine than those not being treated with morphine. Structural nervePatients with sciatica and lumbar CSF 120 proteins disc herniation haveshown high CSF levels of neurofilament protein and S-100 protein, whichare indicators of axonal damage and Schwann cell injury. Markers ofIntervertebral disc damage has been Blood draw 120 collagen shown to becorrelated with an metabolism increase in collagen metabolism, which canbe monitored using serum markers such as PICP and CTX. cystatin CUpregulation of cystatin C has been CSF 120 demonstrated in animalmodels of pain, and higher levels of cystatin C has been found in CSFsamples of patients in pain compared to those not in pain, PurinesFibromyalgia patients show Blood draw 123 abnormal profile of purines inplasma based on activity of enzymes involved in purine metabolism(adenosine deaminase, dipeptidyl peptidase IV and prolyl endopeptidase).Peripheral tissue Peripheral pain mediators are Blood draw, 121 markersreleased in response to damage or Tissue Biopsy disease, and inducesensitization leading to chronic pain. Examples include: ProstanoidsCytokines TNFα and IL-1β Nerve growth factor (NGF) Chemokines includingCCL2, CCL3, and CXCL5 CNS plasticity Central sensitization is anotherstep Blood draw; 121 markers in the process leading to chronic TissueBiopsy pain, and is mediated by NMDA receptors. Gene Expression Alteredgene expression is Blood draw; 121, 122 associated with chronic pain.Tissue Biopsy Affected genes include: Nociceptors e.g., Trp-V1, TrpA1,GABA-B1, 5-HT3A) Ion channels regulating nociceptor excitability (e.g.,Nav1.8 and other sodium channel subunits, potassium channel subunits)Transmitters and modulators released centrally (e.g., substance P, BDNF,neuropeptide Y) μ-opioid receptor Genes involved in GABA synthesis(e.g., GAD65, GAD67, GABA-B1) Human genetic studies have shown acorrelation between GTP cyclohydrolase 1 polymorphisms, which decreasetetrahydrobiopterin (BH4) levels, and reduced pain in patients.Furthermore, excessive BH4 is produced after nerve injury in mice, andblocking the BH4 production reduces hypersensitivity. EpigeneticEpigenetic modifications is Blood draw; 121 modifications associatedwith the development of Tissue Biopsy chronic pain Histone acetylationHistone deacetylase (HDAC) inhibitors (compounds that prevent theremoval of acetyl groups from histones) can mitigate symptoms in animalmodels of inflammatory diseases (e.g., arthritis, colitis, andhepatitis), has also been shown to have clinical benefits arthritis DNAmethylation Methyl binding protein MeCP2 has been shown to promoteabnormal upregulation of a group of genes in inflammatory painconditions intervertebral disc degeneration, and the chronic painassociated with it, has been shown to correlate with increases inmethylation at the SPARC gene promoter in both mice and humans. RESTREST promoter binding is directly responsible for reduced expression ofseveral genes known to be relevant for nociceptive processing in the DRG(e.g., μ- opioid receptor, Nav1.8, Kv4.3).

TABLE 1 Abbreviations used in Table 1. BP Blood Pressure BPV BloodPressure Variability CP Chronic Pain CPT Current Perception Threshold CVCardiovascular EEG Electroencephalography EMG Electromyography EP EvokedPotential FM Fibromyalgia GSR Galvanic Skin Response HR Heart Rate HRVHeart Rate Variability LBP Low Back Pain MSNA Muscle Sympathetic NerveActivity NPV Normalized Pulse Volume NS Not significant OPS ObjectivePain Score PA Plethysmogram Amplitude PPG Plethysmograin PPT PainPerception Threshold PTT Pain Tolerance Threshold QST QuantitativeSensory Testing RSA Respiratory Sinus Arrhythmia SC Skin Conductance SCSSpinal Cord Stimulation SNA Sympathetic Nervous Activity UsEnUltra-short Entropy

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What is claimed is:
 1. A method for managing pain of a patient,comprising: receiving multiple parameters related to the pain; receivingweighting factors; generating a quantitative measure of the painautomatically using a processor, including producing a signal metricusing the multiple parameters each weighted by applying a weightingfactor of the weighting factors, adjusting the weighting factors byautomatic adaptation to the patient over time, and determining thequantitative measure of the pain using the signal metric; delivering oneor more pain-relief therapies using a pain relief device; andcontrolling the delivery of the one or more pain-relief therapies basedon the quantitative measure of the pain.
 2. The method of claim 1,comprising generating the quantitative measure of the pain andcontrolling the delivery of the one or more pain-relief therapies usinga portable device wirelessly coupled to the pain relief device.
 3. Themethod of claim 2, further comprising managing the pain of the patientremotely through a network, including: producing a notification based onthe quantitative measure of the pain using the portable device;transmitting the notification to the network using the portable device;and receiving commands for adjusting the delivery of the one or morepain-relief therapies from the network using the portable device.
 4. Themethod of claim 2, wherein delivering the one or more pain-relieftherapies using the pain relief device comprises delivering spinal cordstimulation using an implantable medical device.
 5. The method of claim2, wherein delivering the one or more pain-relief therapies using thepain relief device comprises delivering deep brain stimulation using animplantable medical device.
 6. The method of claim 1, wherein themultiple parameters comprise one or more mental state parametersindicative of the patient's mental state related to the pain.
 7. Themethod of claim 6, further comprising determining the one or more mentalstate parameters using an input from the patient.
 8. The method of claim6, further comprising determining the one or more mental stateparameters using one or more measures of the patient's neural activitysensed using one or more sensors.
 9. The method of claim 1, wherein themultiple parameters comprise time of day.
 10. The method of claim 1,wherein the multiple parameters comprise one or more environmentalparameters including at least one of temperature, humidity, or airpressure.
 11. A system for managing pain of a patient using a network,comprising: a pain analyzer configured to receive multiple parametersrelated to the pain, to generate weighting factors, to produce a signalmetric using the multiple parameters each weighted by applying aweighting factor of the weighting factors, to adjust the weightingfactors by automatic adaptation to the patient over time, and togenerate a quantitative measure of the pain using the signal metric; apain relief device configured to deliver one or more pain-relieftherapies; and a control circuit configured to control the delivery ofthe one or more pain-relief therapies based on the quantitative measureof the pain.
 12. The system of claim 11, comprising a portable deviceincluding at least the pain analyzer.
 13. The system of claim 12,wherein the portable device comprises a hand-held or wearable device andis configured to: produce a notification based on the quantitativemeasure of the pain; transmit the notification to the network; andreceive commands for adjusting the delivery of the one or morepain-relief therapies from the network.
 14. The system of claim 13,wherein the portable device comprises a smartphone, a laptop computer,or a tablet computer.
 15. The system of claim 12, comprising animplantable medical device configured to be wirelessly coupled to theportable device, the implantable medical device including at least thepain relief device.
 16. The system of claim 15, further comprising: oneor more sensors configured to sense one or more signals from thepatient; one or more sensing circuits configured to process the sensedone or more signals; and one or more parameter generators configured togenerate one or more parameters of the multiple parameters.
 17. Thesystem of claim 11, wherein the pain analyzer is configured to receiveone or more mental state parameters of the multiple parameters, the oneor more mental state parameters indicative of the patient's mental staterelated to the pain.
 18. The system of claim 11, wherein the painanalyzer is configured to receive a time of day of the multipleparameters and to produce the signal metric by including circadianinfluence on the pain.
 19. The system of claim 11, wherein the painanalyzer is configured to receive one or more environmental parametersof the multiple parameters, the environmental parameters including atleast one of temperature, humidity, or air pressure.
 20. Anon-transitory computer-readable storage medium including instructions,which when executed by a system, cause the system to perform a methodfor managing pain of a patient, the method comprising: receivingmultiple parameters related to the pain; receiving weighting factors;generating a quantitative measure of the pain automatically using aprocessor, including producing a signal metric using the multipleparameters each weighted by applying a weighting factor of the weightingfactors, adjusting the weighting factors by automatic adaptation to thepatient over time, and determining the quantitative measure of the painusing the signal metric; and controlling delivery of one or morepain-relief therapies from a pain-relief device based on thequantitative measure of the pain.